Tranexamic acid (1) (trans-4-(aminomethyl)-cyclohexanecarboxylic acid, Cyklokapron®):
is an antifibrinolytic agent that reversibly blocks lysine binding sites on plasminogen and plasmin, and acts to prevent proteolytic degradation of fibrin clots which form in the normal physiologic process of hemostasis. Both plasminogen and plasmin are activators of fibrinolysis and active clot-lysing agents. Tranexamic acid thus helps to stabilize fibrin clots, which in turn maintains coagulation and helps to control bleeding.
Tranexamic acid is used clinically to control excess bleeding, for example, heavy bleeding associated with cardiac surgery, upper gastrointestinal hemorrhage, blood loss in patients with advanced cancer (both acute hemorrhagic events and low-volume chronic bleeding), excessive bleeding that occurs during dental procedures in hemophiliacs, and for heavy bleeding during menstruation, i.e., menorrhagia (see Wellington and Wagstaff, Drugs, 2003, 63, 1417-1433; Dunn and Goa, Drugs, 1999, 57, 1005-1032; Pereira and Phan, The Oncologist, 2004, 9, 561-570).
The importance of the plasminogen/plasmin proteolytic cascade in epidermal biology and pathophysiology is also well appreciated (Kramer et al., Biol. Chem. Hoppe-Seylar, 1995, 3, 131-141). Disruption of the stratum corneum by mechanical or chemical injury induces epidermal proteolytic activity. Topical treatment of human or rodent skin with tranexamic acid significantly accelerates barrier recovery and greatly decreases epidermal hyperplasia, suggesting a role for plasmin inhibitory compounds in promoting epidermal wound healing (Denda et al., J. Invest. Dermatol., 1997, 109, 84-90; Kitamura et al., J. Soc. Cosmet. Chem., 1995, 29, 133-145). Exposure of human skin to ultraviolet radiation causes erythema and pigmentation, with pigmentation resulting from increased melanin production. A role for plasmin in contributing to increased production of arachidonic acid and prostaglandin metabolites in skin following U.V. exposure has also been demonstrated. Topical application of tranexamic acid prevents U.V.—induced pigmentation in vivo through dose-dependent reduction in prostaglandin production (Maeda and Naganuma, J. Photochem. Photobiol. B, 1998, 47, 136-141; Manosroi et al., J. Cosmet. Sci., 2002, 53, 375-386; Suetsugu et al., U.S. Pat. No. 5,690,914).
The plasminogen activation system is also a predominant protease pathway responsible for extracellular matrix (ECM) degradation. Cancer dissemination and metastasis is synonymous with invasive cell migration, a process in which the ECM plays the dual role of the substratum on which the cells move as well as the physical obstacle that the cells have to surpass. To degrade the physical obstacle that the ECM poses in the direction of migration, cells use proteolytic enzymes such as plasminogen and plasmin capable of hydrolyzing the ECM components (Stonelake et al., Br. J. Cancer, 1997, 75, 951-959; Dunbar et al., Expert Opin, Investig. Drugs, 2000, 9, 2085-2092; Sidenius and Blasi, Cancer Metastasis Rev., 2003, 22, 205-222). Plasmin inhibitory compounds such as tranexamic acid, therefore, show utility as anti-metastatic agents either alone or in combination with cytotoxic anticancer agents (Tsutsumi and Konishi, Jpn. Kokai Tokkyo Koho, 2002114673).
Menorrhagia is defined as blood loss >80 mL, per menstrual cycle and affects many women and represents a significant health problem. Prevalence rates are believed to be similar across the Western world, and in the U.K. at least one in 20 women aged between 34 and 49 years will consult their general practitioners because of menstrual disorders. Menorrhagia accounts for 60% of primary-care consultations for menstrual problems and 12% of all gynecology referrals (Peto et al., Fam. Pract., 1993, 10, 207-211; McPherson and Andersson, eds., Women's problems in general practice, Oxford: Oxford University Press, 1983, pp 21-41; Bradlow et al., Patterns of referral, Oxford: Oxford Health Services Research Unit, 1992). While various pathological mechanisms may contribute to the cause of menorrhagia, approximately 50% of women with heavy menstrual blood loss have no underlying anatomical or endocrinological abnormality. In such women fibrinolytic activity in utero is higher than in women with normal menstrual blood loss, with this increased fibrinolysis resulting from elevated levels of endometrium-derived plasmin and plasminogen activators (Gleeson, Am. J. Obstet. Gynecol., 1994, 171, 178-183; Dockeray et al., Eur. J. Obstet. Gynecol. Reprod. Biol., 1987, 24, 309-318).
Despite the availability of clinically effective antifibrinolytic agents such as tranexamic acid (which has been shown to reduce menstrual blood loss by ˜50%), approximately 60% of women with menorrhagia undergo hysterectomy within 5 years of referral to a gynecologist (Coulter et al., Br. J Obstet. Gynaecol., 1991, 98, 789-796). Women suffering from menorrhagia are typically treated orally with tranexamic acid concurrently with menstruation (4-7 days). Doses of 500-1500 mg tranexamic acid tablets administered three or four times daily are typical. Intravenous dosage formulations are also available for use as a continuous infusion in the surgical setting. The requirement for frequent daily oral administration results from the suboptimal pharmacokinetic properties of tranexamic acid, which includes modest oral bioavailability (˜30%) and a rapid terminal elimination half-life of ˜2 hours.
Sustained released oral dosage formulations are a conventional solution to the problem of rapid systemic drug clearance, as is well known in the art (See, e.g., “Remington's Pharmaceutical Sciences,” Philadelphia College of Pharmacy and Science, 19th Edition, 1995). Osmotic delivery systems are also recognized methods for sustained drug delivery (see e.g., Verma et al., Drug Dev. Ind. Pharm., 2000, 26, 695-708). Successful application of these technologies depends on the drug of interest having an effective level of absorption from the large intestine (also referred to herein as the colon), where the dosage form spends a majority of its time during its passage through the gastrointestinal tract. Tranexamic acid is poorly absorbed following rectal administration in humans (Almer et al., J. Clin. Pharm., 1992, 32, 49-54), consistent with limited permeability of the drug across the colonic mucosa. Development of an oral controlled release formulation for tranexamic acid should considerably improve the convenience, efficacy and side effect profile of tranexamic acid therapy. However, the rapid passage of conventional dosage forms through the proximal absorptive region of the small intestine has thus far prevented the successful application of sustained release technologies to this drug. Heasley et al. have described delayed release oral formulations of tranexamic acid based on the use of enteric polymer coatings that are designed to retard the dissolution of the drug by 1-2 hours until the dosage form has passed from the stomach to the small intestine (U.S. Patent Application No. 2005/002825). Such formulations are said to reduce the adverse gastrointestinal reactions that may accompany oral tranexamic acid therapy (including nausea, vomiting, diarrhea, dyspepsia and cramping). However these formulations would not be expected to substantially alter the elimination half-life of the drug, and hence overcome the requirement for frequent daily dosing.
There is a significant need for new prodrugs of tranexamic acid that are well absorbed in the large intestine and hence suitable for oral sustained release formulations, thus improving the convenience, efficacy and side effect profile of antifibrinolytic therapy. Moreover, since the zwitterionic character of tranexamic acid limits the permeability of the compound across the epidermal barrier, there is also a need for more lipophilic prodrug derivatives of tranexamic acid which would provide for more effective topical administration in the treatment of skin disorders such as wound healing, epidermal hyperplasia, skin roughening, unwanted skin pigmentation, etc.
One solution to the incomplete gastrointestinal absorption of tranexamic acid is through design of prodrug derivatives (see Svahn et al., J. Med Chem., 1986, 29, 448-453; Svahn et al., European Patent No. 0 079 872 B 1; Svahn et al., U.S. Pat. No. 4,483,867; Jonsson, International Publication No. WO94/15904; Svahn et al., Arzneim-Forsch., 1988, 38, 735-738; Edlund et al., Br. J. Obstet. Gynaecol., 1995, 102, 913-917). The prodrug 1-(ethoxycarbonyl)oxyethyl trans-4-(aminomethyl)-cyclohexanecarboxylate (i.e., Kabi 2161) showed markedly improved oral bioavailability of tranexamic acid in human patients, and was effective in reducing menstrual blood loss in women suffering from idiopathic menorrhagia.